Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from the gut) and possesses a characteristic amino acid sequence as illustrated by D. F. Veber et al. in U.S. Pat No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine, as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in gastrointestinal disorders and diseases of the GI tract, like ulcerative colitis, irritable bowel syndrome, Crohn's disease, etc. It is also reported that tachykinin antagonists are useful for the treatment of cardiovascular diseases, allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera, senile dementia of the Alzheimer type, emesis, sunburn and Helicobacter pylori infection.
European Patent Application 840,732, which was published on May 13, 1998 and international Patent Application PCT/IB97/01466, filed on Nov. 19, 1997, disclose a variety of substituted piperidine compounds, including piperidine compounds having a substituent comprising a fused ring moiety including an oxygen atom, as substance P antagonists.
Substance P antagonists having improved activity and fewer side effects are desired.